Enterohemorrhagic Shiga toxin-producing E. Coli (EHEC) bacteria are NIAID Biodefense Priority B pathogens and a global health problem. The E. Coli O157:H7 strain is most common and is a recent contaminant of hamburger, spinach, bean sprouts and other foods causing multi-state and multi-country outbreaks. The US burden is ~176,000 infections annually (est. 150 million globally) with significant morbidity, particularl acute kidney injury in young children and the elderly. The hemorrhagic colitis usually resolves, but some patients progress to potentially lethal hemolytic uremic syndrome (HUS), as well as neurologic, pulmonary and cardiac complications. Long-term renal sequelae occur in 25-36% of patients who survive diarrhea- associated HUS. Bacterial toxins (Stx1,Stx2) drive organ damage, yet toxin-specific therapeutics are not available because drug development is hindered by lack of animal models that recapitulate human symptoms, lack of drugs that neutralize toxin within cells, and lack of biomarkers that predict HUS risk or report early renal injury. We have developed the only animal models that develop Stx-induced HUS. Using Rescue Protocols, we will use these models to test the hypothesis that targeting the toxins in the blood and already within cells with adjunctive therapeutics will prevent or mitigate development of Stx-induced HUS, and that Stx- induced biomarkers can report organ injury to identify those at high risk for HUS. We predict that targeting toxins in one or both compartments will reduce acute kidney injury and minimize disease severity. Intracellular toxins will be targeted with custom designed cell permeable peptides (Aim1) and intravascular toxin will be targeted with a patented humanized anti-Stx2 monoclonal antibody (Aim2). Studies are designed to maximize delayed administration of drug while maintaining efficacy. New and established biomarkers will be correlated with experimental clinical results to identify molecules that report early and sustained kidney injury, and HUS risk. Our combination of clinically relevant animal models with systemic and intracellular toxin targeting compounds is a powerful approach to move the field forward toward targeted patient treatment.